Discussion
Immune-mediated necrotizing myopathy (IMNM) can be caused by cancer,
viral infection, connective tissue diseases, and medications, especially
statin, anti-HMGCR, and anti-SRP autoantibodies, resulting in skeletal
muscle injury3. Antibodies against HMGCR, the statins
target, are found more often in patients with necrotizing myopathy with
statin exposure; thus, the positive antibody supports the autoimmune
process2. There have been many proposed mechanisms for
the pathogenesis underlying the statin-induced IMNM; however, the true
mechanism is not well understood 2,4.
Anti-HMGCR IMNM presents clinically as a subacute or chronic progressive
symmetrical proximal muscle weakness. Dysphagia, like our patient,
occurs in approximately one-third of patients. Muscle weakness persists
despite discontinuing statins and CK levels, usually exceeding 10 times
the upper normal limit1,2. Extramacular manifestations
like those of dermatomyositis can be present5.
However, malignancy-associated anti-HMGCR IMNM was unclear; there was no
statistically significant relation6,7.
Musculoskeletal MRI and EMG can be done prior to antibody assay or
muscle biopsy. EMG usually shows signs of irritable myopathic patterns
but is not possible to differentiate the type of inflammatory myositis.
MRI with STIR sequence in statin-induced IMNM demonstrates diffuse and
symmetrical muscle edema and signs of fibro-adipose tissue
replacement2,3. A report by Mammen proposed an
algorithm for evaluating potential cases of statin-associated autoimmune
myopathy2. The presence of muscle necrosis and
regeneration with sparse inflammatory infiltrates on muscle biopsy are
the prominent histologic features2.
There is no definite cutoff point on how long after taking statins
patients would develop IMNM—it can range from months to
years8. In our case, the patient developed weakness a
few months after statin initiation and continued to deteriorate even
after statin discontinuation. Compared to other statins, atorvastatin
was more frequently reported to be a cause of statin-induced IMNM,
likely due to its high lipophilic property resulting in better
penetration to peripheral and liver tissues9. Symptoms
are milder at onset 50-60 years old while younger patients appear to be
more severe and, regardless of statin use, are more recalcitrant to
treatment.7
Serum levels of the anti-HMGCR antibody are correlated with creatinine
kinase and inversely associated with the degree of muscle
weakness7,10. However, anti-HMGCR titers remain
positive even in the remission of the disease and CK level normalizes.
Together with being a more expensive test, there is no need to monitor
anti-HMGCR levels practically7.
No definite guideline has been available on how long a patient should be
on the treatment. The first step is to discontinue statins. Unlike
self-limited forms of statin myopathy, statin-induced IMNM very rarely
improves spontaneously after stopping statins. Only a few reported
statin-induced IMNM patients with positive anti-HMGCR antibodies
spontaneously resolved2. The most common therapy is
prednisolone combined with at least another agent like methotrexate,
azathioprine, or mycophenolate mofetil5,6,8. IVIg or
rituximab can be added to support the treatment but preferentially
IVIG3,11,12 Our case, the patient received triple
therapy which comprises IVIg, systemic corticosteroids, and a
non-steroidal immunosuppressant, which has been described as in the
literature2,5. Symptom resolution time was
approximately twelve months and might take longer in females at 16
months9. Most of the patients responded well to
immunosuppressive treatment. Symptoms monitoring is required following
tapering doses of immunosuppressants due to the autoimmunity which may
cause disease relapse.
Statins are contraindicated in this group of patients. To substitute the
need for statins, aside from fenofibrate or ezetimibe, proprotein
convertase subtilisin/kexin type 9 (PCSK9) inhibitors can be used and
are safe in patients with anti-HMGCR myopathy9.